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Debra A. Tanguay^*, Thomas P. Colarusso^,||, Sandra Pavlovic^*, Macarena Irigoyen^,||, Robert G. Howard^,||, Jiri Bartek^¶, Thomas C. Chiles^*, and Thomas L. Rothstein^,,||

From the ^* Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467; the Department of Medicine, the Department of Microbiology, and ^|| The Evans Memorial Department of Clinical Research, Boston University Medical Center, Boston, Massachusetts 02118; and the ^¶ Division of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark DK-2100

B-1 lymphocytes represent a distinct B cell subset with characteristic features that include self-renewing capacity and unusual mitogenic responses. B-1 cells differ from conventional B cells in terms of the consequences of phorbol ester treatment: B-1 cells rapidly enter S phase in response to phorbol ester alone, whereas B-2 cells require a calcium ionophore in addition to phorbol ester to trigger cell cycle progression. To address the mechanism underlying the varied proliferative responses of B-1 and B-2 cells, we evaluated the expression and activity of the G1 cell cycle regulator, cyclin D2, and its associated cyclin-dependent kinases (Cdks). Cyclin D2 expression was upregulated rapidly, within 2–4 h, in phorbol ester–stimulated B-1 cells, in a manner dependent on intact transcription/translation, but was not increased in phorbol ester– stimulated B-2 cells. Phorbol ester–stimulated cyclin D2 expression was accompanied by the formation of cyclin D2–Cdk4, and, to a lesser extent, cyclin D2–Cdk6, complexes; cyclin D2– containing complexes were found to be catalytically functional, in terms of their ability to phosphorylate exogenous Rb in vitro and to specifically phosphorylate endogenous Rb on serine⁷⁸⁰ in vivo. These results strongly suggest that the rapid induction of cyclin D2 by a normally nonmitogenic phorbol ester stimulus is responsible for B-1 cell progression through G1 phase. The ease and rapidity with which cyclin D2 responds in B-1 cells may contribute to the proliferative features of this subset.

Key Words: B lymphocytes • B-1 cells • B-2 cells • cyclins • cyclin-dependent kinases

D.A. Tanguay's present address is Department of Microbiology, Boston University School of Medicine, 80 East Concord St., Boston, MA 02118.

Abbreviations used: Cdk, cyclin-dependent kinase; DTT, dithiothreitol; GAPDH, glyceraldehyde-6-phosphate dehydrogenase; sIg, surface immunoglobulin; STAT, signal transducer and activator of transcription.

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